Pyrazolopyridine pyrimidone hybrids as potential DprE1 inhibitors, design, synthesis and biological evaluation as...

Tuberculosis (TB) remains a major global health challenge. This study presents the design, synthesis, and evaluation of some novel pyrazolo[3,4-b]pyridine-pyrimidone derivatives targeting Mycobacterium tuberculosis (Mtb). The compounds were assessed for anti-tubercular activity using the Microplate Alamar Blue Assay (MABA) against the Mtb H37Rv strain. Key derivatives (8 and 14) showed significant activity with minimum inhibitory concentration (MIC) values of 3.12 µg/mL, 12.5 µg/mL, respectively, comparable to the standard drugs and are nontoxic at their effective concentration as anti-TB agents. Molecular docking studies demonstrated strong binding interactions with DprE1 and Mtb-DHFR enzymes, suggesting inhibition of these critical proteins. Further computational analyses, including density functional theory (DFT) and molecular dynamics simulations, confirmed the binding stability of the compounds to the target proteins. Overall, these pyrazolo[3,4-b]pyridine-pyrimidone derivatives are potential leads for further development as future therapeutics for treating drug-resistant TB.